1. Field of the Invention
The invention relates to inhibitors of the nucleic enzyme poly(adenosine 5'-diphospho-ribose)polymerase ["poly(ADP-ribose)polymerase" or "PARP", which is also sometimes called "PARS" for poly(ADP-ribose) synthetase]. More particularly, the invention also relates to the use of PARP inhibitors to prevent and/or treat neural tissue damage resulting from ischemia and reperfusion injury, neurological disorders and other neurodegenerative diseases; to prevent or treat vascular stroke; to treat or prevent cardiovascular disorders; or to treat other disorders such as arthritis, diabetes, septic shock (such as endotoxic shock); inflammatory disorders of the bowel (such as colitis and Crohn's disease); and cancer.
2. Description of the Prior Art
Poly(ADP-ribose)polymerase ("PARP") is an enzyme located in the nuclei of cells of various organs, including muscle, heart and brain cells. PARP plays a physiological role in the repair of strand breaks in DNA. Once activated by damaged DNA fragments, PARP catalyzes the attachment of up to 100 ADP-ribose units to a variety of nuclear proteins, including histones and PARP itself. While the exact range of functions of PARP has not been fully established, this enzyme is thought to play a role in enhancing DNA repair.
During major cellular stresses, however, the extensive activation of PARP can rapidly lead to cell death through depletion of energy stores. Four molecules of ATP are consumed for every molecule of NAD (the source of ADP-ribose) regenerated. Thus, NAD, the substrate of PARP, is depleted by massive PARP activation and, in the efforts to re-synthesize NAD, ATP may also be depleted.
It has been reported that PARP activation plays a key role in both NMDA- and NO-induced neurotoxicity, as shown by the use of PARP inhibitors to prevent such toxicity in cortical cultures in proportion to their potencies as inhibitors of this enzyme (Zhang et al., "Nitric Oxide Activation of Poly(ADP-Ribose) Synthetase in Neurotoxicity", Science, 263:687-89 (1994)); and in hippocampal slices (Wallis et al., "Neuroprotection Against Nitric Oxide Injury with Inhibitors of ADP-Riboslation", NeuroReport, 5:3, 245-48 (1993)). The potential role of PARP inhibitors in treating neurodegenerative diseases and head trauma has thus been known. Research, however, continues to pinpoint the exact mechanisms of their salutary effect in cerebral ischemia (Endres et al., "Ischemic Brain Injury is Mediated by the Activation of Poly(ADP-Ribose)-Polymerase", J. Cereb. Blood Flow Metabol., 17:1143-51 (1997)) and in traumatic brain injury (Wallis et al., "Traumatic Neuroprotection with Inhibitors of Nitric Oxide and ADP-Ribosylation, Brain Res., 710:169-77 (1996)).
It has been demonstrated that single injections of PARP inhibitors have reduced the infarct size caused by ischemia and reperfusion of the heart or skeletal muscle in rabbits. In these studies, a single injection of the PARP inhibitor, 3-aminobenzamide (10 mg/kg), either one minute before occlusion or one minute before reperfusion, caused similar reductions in infarct size in the heart (32-42%). Another PARP inhibitor, 1,5-dihydroxy-isoquinoline (1 mg/kg), reduced infarct size by a comparable degree (38-48%). Thiemermann et al., "Inhibition of the Activity of Poly(ADP Ribose) Synthetase Reduces Ischemia-Reperfusion Injury in the Heart and Skeletal Muscle", Proc. Natl. Acad. Sci. USA, 94:679-83 (1997). This finding has suggested that PARP inhibitors might be able to salvage previously ischemic heart or skeletal muscle tissue.
PARP activation has also been shown to provide an index of damage following neurotoxic insults by glutamate (via NMDA receptor stimulation), reactive oxygen intermediates, amyloid .beta.-protein, n-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and its active metabolite N-methyl-4-phenylpyridine (MPP.sup.+), which participate in pathological conditions such as stroke, Alzheimer's disease and Parkinson's disease. Zhang et al., "Poly(ADP-Ribose) Synthetase Activation: An Early Indicator of Neurotoxic DNA Damage", J. Neurochem., 65:3, 1411-14 (1995). Other studies have continued to explore the role of PARP activation in cerebellar granule cells in vitro and in MPTP neurotoxicity. Cosi et al., "Poly(ADP-Ribose) Polymerase (PARP) Revisited. A New Role for an Old Enzyme: PARP Involvement in Neurodegeneration and PARP Inhibitors as Possible Neuroprotective Agents", Ann. N. Y. Acad. Sci., 825:366-79 (1997); and Cosi et al., "Poly(ADP-Ribose) Polymerase Inhibitors Protect Against MPTP-induced Depletions of Striatal Dopamine and Cortical Noradrenaline in C57B1/6 Mice", Brain Res., 729:264-69 (1996).
Neural damage following stroke and other neurodegenerative processes is thought to result from a massive release of the excitatory neurotransmitter glutamate, which acts upon the N-methyl-D-aspartate (NMDA) receptors and other subtype receptors. Evidence includes findings in many animal species, as well as in cerebral cortical cultures treated with glutamate or NMDA, that glutamate receptor antagonists block neural damage following vascular stroke. Dawson et al., "Protection of the Brain from Ischemia", Cerebrovascular Disease, 319-25 (H. Hunt Batjer ed., 1997).
The stimulation of NMDA receptors, in turn, activates the enzyme neuronal nitric oxide synthase (NNOS), which causes the formation of nitric oxide (N,O), which more directly mediates neurotoxicity. Protection against NMDA neurotoxicity has occurred following treatment with NOS inhibitors. See Dawson et al., "Nitric Oxide Mediates Glutamate Neurotoxicity in Primary Cortical Cultures", Proc. Natl. Acad. Sci. USA, 88:6368-71 (1991); and Dawson et al., "Mechanisms of Nitric Oxide-mediated Neurotoxicity in Primary Brain Cultures", J. Neurosci., 13:6, 2651-61 (1993). Protection against NMDA neurotoxicity can also occur in cortical cultures from mice with targeted disruption of NNOS. See Dawson et al., "Resistance to Neurotoxicity in Cortical Cultures from Neuronal Nitric Oxide Synthase-Deficient Mice", J. Neurosci., 16:8, 2479-87 (1996).
It is known that neural damage following vascular stroke is markedly diminished in animals treated with NOS inhibitors or in mice with NNOS gene disruption. Iadecola, "Bright and Dark Sides of Nitric Oxide in Ischemic Brain Injury", Trends Neurosci., 20:3, 132-39 (1997); and Huang et al., "Effects of Cerebral Ischemia in Mice Deficient in Neuronal Nitric Oxide Synthase", Science, 265:1883-85 (1994). See also, Beckman et al., "Pathological Implications of Nitric Oxide, Superoxide and Peroxynitrite Formation", Biochem. Soc. Trans., 21:330-34 (1993). Either NO or peroxynitrite can cause DNA damage, which activates PARP. Further support for this is provided in Szaboet al., "DNA Strand Breakage, Activation of Poly(ADP-Ribose) Synthetase, and Cellular Energy Depletion are Involved in the Cytotoxicity in Macrophages and Smooth Muscle Cells Exposed to Peroxynitrite", Proc. Natl. Acad. Sci. USA, 93:1753-58 (1996).
Zhang et al., U.S. Pat. No. 5,587,384 issued Dec. 24, 1996, discusses the use of certain PARP inhibitors, such as benzamide and 1,5-dihydroxy-isoquinoline, to prevent NMDA-mediated neurotoxicity and, thus, treat stroke, Alzheimer's disease, Parkinson's disease and Huntington's disease. However, it has now been discovered that Zhang et al. may have been in error in classifying in vivo neurotoxicity as NMDA-mediated neurotoxicity. Rather, it may have been more appropriate to classify the neurotoxicity as glutamate neurotoxicity. See Zhang et al., "Nitric Oxide Activation of Poly(ADP-Ribose) Synthetase in Neurotoxicity", Science, 263:687-89 (1994). See also, Cosi et al., Poly(ADP-Ribose)-Polymerase Inhibitors Protect Against MPTP-induced Depletions of Striatal Dopamine and Cortical Noradrenaline in C57B1/6 Mice", Brain Res., 729:264-69 (1996).
It is also known that PARP inhibitors effect DNA repair generally. Cristovao et al., "Effect of a Poly(ADP-Ribose)Polymerase Inhibitor on DNA Breakage and Cytotoxicity Induced by Hydrogen Peroxide and .gamma.-Radiation," Terato., Carcino., Muta., 16:219-27 (1996), discusses the effect of hydrogen peroxide and .gamma.-radiation on DNA strand breaks in the presence of and in the absence of 3-aminobenzamide, a potent inhibitor of PARP. Cristovao et al. observed a PARP-dependent recovery of DNA strand breaks in leukocytes treated with hydrogen peroxide.
Evidence also exists that PARP inhibitors are useful for treating inflammatory bowel disorders. Salzman et al., "Role of Peroxynitrite and Poly(ADP-Ribose)Synthase Activation Experimental Colitis," Japanese J. Pharm., 75, Supp. I:15 (1997), discusses the ability of PARP inhibitors to prevent or treat colitis. Colitis was induced in rats by intraluminal administration of the hapten trinitrobenzene sulfonic acid in 50% ethanol. Treated rats received 3-aminobenzamide, a specific inhibitor of PARP activity. Inhibition of PARP activity reduced the inflammatory response and restored the morphology and the energetic status of the distal colon. See also, Southan et al., "Spontaneous Rearrangement of Aminoalkylthioureas into Mercaptoalkylguanidines, a Novel Class of Nitric Oxide Synthase Inhibitors with Selectivity Towards the Inducible Isoform", Br. J. Pharm., 117:619-32 (1996); and Szabo et al., "Mercaptoethylguanidine and Guanidine Inhibitors of Nitric Oxide Synthase React with Peroxynitrite and Protect Against Peroxynitrite-induced Oxidative Damage", J. Biol. Chem., 272:9030-36 (1997).
Evidence also exists that PARP inhibitors are useful for treating arthritis. Szabo et al., "Protective Effects of an Inhibitor of Poly(ADP-Ribose)Synthetase in Collagen-Induced Arthritis," Japanese J. Pharm., 75, Supp. I:102 (1997), discusses the ability of PARP inhibitors to prevent or treat collagen-induced arthritis. See also, Szabo et al., "DNA Strand Breakage, Activation of Poly(ADP-Ribose)Synthetase, and Cellular Energy Depletion are Involved in the Cytotoxicity in Macrophages and Smooth Muscle Cells Exposed to Peroxynitrite," Proc. Natl. Acad. Sci. USA, 93:1753-58 (March 1996); Bauer et al., "Modification of Growth Related Enzymatic Pathways and Apparent Loss of Tumorigenicity of a ras-transformed Bovine Endothelial Cell Line by Treatment with 5-Iodo-6-amino-1,2-benzopyrone (INH.sub.2 BP)", Intl. J. Oncol., 8:239-52 (1996); and Hughes et al., "Induction of T Helper Cell Hyporesponsiveness in an Experimental Model of Autoimmunity by Using Nonmitogenic Anti-CD3 Monoclonal Antibody", J. Immuno., 153:3319-25 (1994).
Further, PARP inhibitors appear to be useful for treating diabetes. Heller et al., "Inactivation of the Poly(ADP-Ribose)Polymerase Gene Affects Oxygen Radical and Nitric Oxide Toxicity in Islet Cells," J. Biol. Chem., 270:19, 11176-80 (May 1995), discusses the tendency of PARP to deplete cellular NAD+ and induce the death of insulin-producing islet cells. Heller et al. used cells from mice with inactivated PARP genes and found that these mutant cells did not show NAD+ depletion after exposure to DNA-damaging radicals. The mutant cells were also found to be more resistant to the toxicity of NO.
Further still, PARP inhibitors have been shown to be useful for treating endotoxic shock or septic shock. Zingarelli et al., "Protective Effects of Nicotinamide Against Nitric Oxide-Mediated Delayed Vascular Failure in Endotoxic Shock: Potential Involvement of PolyADP Ribosyl Synthetase," Shock, 5:258-64 (1996), suggests that inhibition of the DNA repair cycle triggered by poly(ADP ribose) synthetase has protective effects against vascular failure in endotoxic shock. Zingarelli et al. found that nicotinamide protects against delayed, NO-mediated vascular failure in endotoxic shock. Zingarelli et al. also found that the actions of nicotinamide may be related to inhibition of the NO-mediated activation of the energy-consuming DNA repair cycle, triggered by poly(ADP ribose) synthetase. See also, Cuzzocrea, "Role of Peroxynitrite and Activation of Poly(ADP-Ribose) Synthetase in the Vascular Failure Induced by Zymosan-activated Plasma," Br. J. Pharm., 122:493-503 (1997).
Yet another known use for PARP inhibitors is treating cancer. Suto et al., "Dihydroisoquinolinones: The Design and Synthesis of a New Series of Potent Inhibitors of Poly(ADP-Ribose) Polymerase", Anticancer Drug Des., 7:107-17 (1991), discloses processes for synthesizing a number of different PARP inhibitors. In addition, Suto et al., U.S. Pat. No. 5,177,075, discusses several isoquinolines used for enhancing the lethal effects of ionizing radiation or chemotherapeutic agents on tumor cells. Weltin et al., "Effect of 6(5H)-Phenanthridinone, an Inhibitor of Poly(ADP-ribose) Polymerase, on Cultured Tumor Cells", Oncol. Res., 6:9, 399-403 (1994), discusses the inhibition of PARP activity, reduced proliferation of tumor cells, and a marked synergistic effect when tumor cells are co-treated with this compound and an alkylating drug.
Large numbers of known PARP inhibitors have been described in Banasik et al., "Specific Inhibitors of Poly(ADP-Ribose) Synthetase and Mono(ADP-Ribosyl)-Transferase", J. Biol. Chem., 267:3, 1569-75 (1992), and in Banasik et al., "Inhibitors and Activators of ADP-Ribosylation Reactions", Molec. Cell. Biochem., 138:185-97 (1994). The former reference discloses 6(5H)-phenanthridinone and 2-nitro-6(5H)-phenanthridinone.
However, the approach of using these PARP inhibitors to reduce NMDA-receptor stimulation, or to treat or prevent neural tissue damage caused by NO, ischemia and reperfusion of the heart, arthritis, diabetes, endotoxic or septic shock, inflammatory diseases of the bowel (such as colitis and Crohn's disease), and cancer, has been limited in effect. For example, side effects have been observed with some of the best-known PARP inhibitors, as discussed in Milam et al., "Inhibitors of Poly(Adenosine Diphosphate-Ribose) Synthesis: Effect on Other Metabolic Processes", Science, 223:589-91 (1984). Specifically, the PARP inhibitors 3-aminobenzamide and benzamide not only inhibited the action of PARP but also were shown to affect cell viability, glucose metabolism, and DNA synthesis. Thus, it was concluded that the usefulness of these PARP inhibitors may be severely restricted by the difficulty of finding a dose small enough to inhibit the enzyme without producing additional metabolic effects.
Accordingly, there remains a need for a composition containing PARP inhibitors that produce more potent and reliable effects, particularly with respect to vascular stroke, with fewer side effects.
Multicyclic oxo-substituted compounds other than the compounds of the invention are known. These include, but are not limited to:
I. 3-(5-Hexynyl)-2,4a,5,6,7,7a-hexahydro-1H-cyclopenta[c]-pyridin-1-one, shown in Rougeot et al., "Cyclization Reactions of 2-pentynyl-4-pyrimidinones", J. Heterocycl. Chem., 20:5, 1407-9 (1983); PA0 II. 2,4a,5,6,7,7a-Hexahydro-3-methyl-1H-cyclopenta-[c]pyridin-1-one, shown in Davies et al., "Intramolecular Cycloaddition Reactions of Mono- and Dihydroxy-pyrimidines", J. Chem. Soc., 11:1293-97 (1978); PA0 III. 2,4a,5,6,7,7a-Hexahydro-3-phenyl--1H-cyclopenta-[c]pyridin-1-one, shown in Davies et al., "Intramolecular Cycloaddition Reactions of Mono- and Dihydroxy-pyrimidines", J. Chem. Soc., 11:1293-97 (1978); PA0 IV. Octahydro-3-methyl-1(2H)-isoquinolinone, shown in Ochiai et al., "Polarization of Heterocyclic Rings with Aromatic Character. CXLVII. Reaction of 3-Methyl-5,6,7,8-tetrahydroisoquinoline-2-oxide with Acetic Anhydride", Itsuu Kenkusho Nempo, 16:15-23 (1971); PA0 V. Octahydro-&lt;2&gt;pyrindin-1-one, shown in Granger et al., Bull. Soc. Chim. Fr., 233, (1962); PA0 VI. Octahydro-isocarbostyril, shown in: PA0 VII. 3,5-Dihydro--1H-thieno&lt;3,4-c&gt;quinolin-4-one shown in: PA0 VIII. 7(or 9)-Chloro-1,2,3,5-tetrahydro-4H-cyclopenta-[c]quinoline-4-one, 1,2,3,4-tetrahydro-7(or 9)-methyl-4H-cyclopenta[c]quinoline-4-one and 1,2,3,5-tetrahydro-4H-cyclopenta[c]quinolin-4-one, shown in: PA0 IX. 2-Hydroxy-3,4-cyclopentenoquinoline, shown in Johnson, "The Synthesis of N-Alkyl-2-Oxocyclopentane-Carboxyamides", J. Chem. Soc., 1624-28 (1958); PA0 X. 1,2,4,6-Tetrahydro-5H-thiopyrano[3,4-c]quinoline-5-one, shown in Castan et al., "New Arylpiperazine Derivatives with High Affinity for 5-HT.sub.3 Receptor Sites", Med. Chem. Soc., 6:2, 81-101 (1996); PA0 XI. 6a,7,8,9,10,10a-Hexahydro-trans-6(5H)-phenanthridinone, shown in: PA0 XII. 7,8,9,10-tetrahydro-65(H), as shown in PA0 XIII. 1,2,3,3a,5,9b-Hexahydro-cyclopenta&lt;c&gt;quinolin-4-one, shown in Blount et al., "Stereoisomerism in Polycyclic Systems. Part VI.", J. Chem. Soc., 1979, 1984 (1929).
(a) Di Maio et al., "Photochemistry of Some N-hydroxy Lactams", Ric. Sci., 38:3, 231-33 (1968); PA1 (b) Di Maio et al., "The Action of Hyponitrous Acid on Ketonic Compounds. II. 1-Hydrinadanone", Gazz. Chim. Ital., 91:1124-32 (1961); PA1 (c) Di Maio et al., "Ring Enlargement: The Schmidt Reaction on 1-hydrindanone", Gazz. Chim. Ital., 91:1345-51 (1961) PA1 (d) Di Maio et al., "The Behavior of Some Cyclic Hydroxamic Acids at Elevated Temperatures", Gazz. Chim. Ital., 94:5, 590-94 (1964); PA1 (e) Baer et al., "Cyclizations of Dialdehydes with Nitromethane. XII. Phthalaldehyde", J. Org. Chem., 29:11, 3180-85 (1964); PA1 (f) Ochiai et al., "Polarization of Aromatic Heterocyclic Compounds. CXX. A New Synthesis of 1-Halo-5,6,7,8-tetrahydroisoquinoline", Pharm. Bull., 5:289-91 (1957); and PA1 (g) Baer et al., "Synthesis of the Isoquinoline System from o-Phthalaldehyde and Nitromethane", Angew. Chem., 76:1, 50 (1964); PA1 (a) White et al., "Quinoline Analogues of Ortho-Quinodimethane", Tetrahedron Letters, 36:33, 5983-86 (1995); and PA1 (b) White et al., "Dihydrothiophenes as Precursors to Fused Quinolines, Quinolones and Coumarins via o-Quinodimethane Intermediates", Tetrahedron, 52:9, 3117-34 (1996); PA1 (a) Brown et al., "Reaction of Ethyl 2-Oxocyclopentane-carboxylate with Arylamines. Part I. The Preparation of 2,3-dihydro-.alpha.-quinindones (2,3,4,5-tetrahydro-4-oxo-1H-cyclopenta[c]quinolines)", J. Chem. Soc., 4295-98 (1961); PA1 (b) 1,2,3,5-Tetrahydro-4H-cyclopenta-[c]quinoline-4-one, Reisch, "Chemistry of Natural Substances. VII. Furoquinoline Derivatives By Condensation of Ethyl 2-Propynyl Malonate with Aromatic Amines", Arch. Pharm. Ber. Dtsch. Pharm. Ges., 300:6, 533-39 (1967); PA1 (c) 1,2,3,5-Tetrahydro-4H-cyclopenta-[c]quinoline-4-one, Eisch et al., "Studies on Nonpyridinoid Azaaromatic Systems. 7. Synthesis and Tautomeric Character of Cyclopenta[c]quinoline (benzo [c] [2]pyrindine)", J. Org. Chem., 43:11, 2190-96 (1978); PA1 (d) 1,2,3,5-Tetrahydro-4H-cyclopenta-[c]quinoline-4-one, Castan et al., "New Arylpiperazine Derivatives with High Affinity for 5-HT.sub.3 Receptor Sites", Med. Chem. Res., 6:2, 81-101 (1996); PA1 (e) 1,2,3,5-Tetrahydro-4H-cyclopenta-[c]quinoline-4-one, Reid et al., "Reactions of Cyclic Enamines. III. Synthesis of N-Heterocycles from Cycloalkenylamine-isocyanate or -isothiocyanate Adducts", Ann. Chem., 688:177-88 (1965); and PA1 (f) 1,2,3,5-Tetrahydro-4H-cyclopenta[c]quinoline-4-one, Reid et al., "Reactions with Cyclic Enamines. I. Reaction of Cycloalkene-amines with Phenyl Isocyanate and Phenylisothiocyanate", Ann., 673:132-36 (1964); PA1 (a) Masamune et al., "Condensed Polynuclear Perhydro Compounds Containing Nitrogen. XII. Synthesis and Exhaustive Methylation of 5,6,6a,7,8,9,10,10a-Octahydro-phenanthridines and Related Compounds", J. Org. Chem., 29:3, 681-85 (1964); PA1 (b) 6a,7,8,9,10,10a-Hexahydro-cis(.+-.)6(5H)-phenanthridinone, Naito et al., "Asymmetric Photocyclization of N-.alpha., .beta.-Unsaturated Acylanilides", Heterocycles, 22:2, 237-40 (1934), along with the (6aR-trans)- and (6aS-trans)-stereoisomers of the same compound; PA1 (c) Michailidis et al., "Hexahydrogenated Derivatives of Phenanthridone Obtained by Birch Reaction", C. R. Acad. Sci., 275:17, 961-64 (1972), with cis and trans stereoisomers of the same compound; PA1 (d) Ninomiya et al., "Photocyclization of Enamides. V. Photocyclization of .alpha., .beta.-Unsaturated Anilides", J. Chem. Soc., 1:14, 1747-51 (1974), with cis stereoisomer; and PA1 (e) Taylor et al., "Phenanthridine Syntheses Via the Diels-Alder Reaction. A New Route to 6(5)-Phenanthridinone", J. Am. Chem. Soc., 78:5104-8 (1956); PA1 (a) Masamune et al., "The Synthesis and Exhaustive Methylation of 5,6,7,8,9,10,6a,10a-Octahydro-phenanthridines and Related Compounds, J. Org. Chem., 29:3, 681-85 (1964); PA1 (b) Bailey et al., "Reactions of p-Toluenesulfonyl Azide with Derivatives of Cyclohept- and Cyclooctindole, J. Chem. Soc., 1:7, 763-70 (1974); PA1 (c) Reid et al., "Reactions of Cyclic Enamines. III. Synthesis of N-Heterocycles from Cycloalkenylamine-isocyanate or -isothiocyanate Adducts", Ann. Chem., 688:177-88 (1965); and PA1 (d) Reid et al., "Reactions with Cyclic Enamines. I. Reaction of Cycloalkene-amines with Phenyl Isocyanate and Phenylisothiocyanate", Ann., 132-36 (1964); and PA1 (1) Taylor et al., "Phenanthridine Syntheses Via the Diels-Alder Reaction. A New Route to 6(5)-Phenanthridinone", J. Am. Chem. Soc., 78:5104-8 (1956); PA1 (2) Reid et al., "Reactions of Cyclic Enamines. III. Synthesis of N-Heterocycles from Cycloalkenylamine-isocyanate or -isothiocyanate Adducts", Ann. Chem., 688:177-88 (1965); PA1 (3) Gauthier, U.S. Pat. No. 3,838,134, disclosing phenanthridinones used as antiviral agents; and PA1 (4) Winter et al., U.S. Pat. No. 4,382,943, disclosing anti-allergic aryl ether derivatives. It is not believed that any of these oxo-substituted compounds have been shown to inhibit PARP activity. PA1 X is double-bonded oxygen or --OH; PA1 when R.sup.7 is present, it is hydrogen or lower alkyl; PA1 Y represents the atoms necessary to form a fused mono-, bi -or tricyclic, carbocyclic or heterocyclic ring, wherein each individual ring has 5-6 ring member atoms; and PA1 Z is (i) --CHR.sup.2 CHR.sup.3 -- wherein R.sup.2 is in the meta-position and R.sup.3 is in the ortho-position relative to said ring nitrogen of formula I, and R.sup.2 and R.sup.3 are independently hydrogen, alkyl, aryl, or aralkyl; PA1 with the provisos that: PA1 (a) when X is double-bonded oxygen and Z is --CHR.sup.2 CHR.sup.3 --, R.sup.3 cannot be hydrogen or methyl; PA1 (b) when X is double-bonded oxygen and Z is --R.sup.6 C.dbd.CR.sup.3 --, R.sup.3 cannot be methyl, phenyl, or --(CH.sub.2).sub.4 --C.tbd.CH; PA1 (c) when R.sup.3 and R.sup.6 are taken together to form a fused aromatic ring, Y cannot be a ring selected from the group consisting of: ##STR4## PA1 (d) when X, Y and Z, taken together, form a phenanthridone, a phenanthridinone, a phenanthrene, or a phenanthridine nucleus with an amino group or an aminoalkoxylene group in the 3-position, the 8-position cannot also be substituted with an amino group or an aminoalkoxylene group; and PA1 (e) when X, Y and Z, taken together, form a phenanthridinone ring system, the 2-position cannot be either unsubstituted or substituted with a nitro group. PA1 X is double-bonded oxygen or --OH; PA1 when R.sup.7 is present, it is hydrogen or lower alkyl; PA1 Y represents the atoms necessary to form a fused mono-, bi- or tricyclic, carbocyclic or heterocyclic ring, wherein each individual ring has 5-6 ring member atoms; and PA1 Z is (i) --CHR.sup.2 CHR.sup.3 -- wherein R.sup.2 is in the meta-position and R.sup.3 is in the ortho-position relative to said ring nitrogen of formula I, and R.sup.2 and R.sup.3 are independently hydrogen, alkyl, aryl, or aralkyl; PA1 with the provisos that: PA1 (a) when X is double-bonded oxygen and Z is --CHR.sup.2 CHR.sup.3 --, R.sup.3 cannot be hydrogen or methyl; PA1 (b) when X is double-bonded oxygen and Z is --R.sup.6 C.dbd.CR.sup.3 --, R.sup.3 cannot be methyl, phenyl, or --(CH.sub.2).sub.4 --C.tbd.CH; PA1 (c) when R.sup.3 and R.sup.6 are taken together to form a fused aromatic ring, Y cannot be a ring selected from the group consisting of: ##STR8## PA1 (d) when X, Y and Z, taken together, form a phenanthridone, a phenanthridinone, a phenanthrene, or a phenanthridine nucleus with an amino group or an aminoalkoxylene group in the 3-position, the 8-position cannot also be substituted with an amino group or an aminoalkoxylene group; and PA1 (e) when X, Y and Z, taken together, form a phenanthridinone ring system, the 2-position cannot be either unsubstituted or substituted with a nitro group. PA1 X is double-bonded oxygen or --OH; PA1 when R.sup.7 is present, it is hydrogen or lower alkyl; PA1 Y represents the atoms necessary to form a fused mono-, bi- or tricyclic, carbocyclic or heterocyclic ring, wherein each individual ring has 5-6 ring member atoms; and PA1 Z is (i) --CHR.sup.2 CHR.sup.3 -- wherein R.sup.2 is in the meta-position and R.sup.3 is in the ortho-position relative to said ring nitrogen of formula I, and R.sup.2 and R.sup.3 are independently hydrogen, alkyl, aryl, or aralkyl; PA1 with the provisos that: PA1 (a) when X is double-bonded oxygen and Z is --CHR.sup.2 CHR.sup.3 --, R.sup.3 cannot be hydrogen or methyl; PA1 (b) when X is double-bonded oxygen and Z is --R.sup.6 C.dbd.CR.sup.3 --, R.sup.3 cannot be methyl, phenyl, or --(CH.sub.2).sub.4 --C.tbd.CH; PA1 (c) when R.sup.3 and R.sup.6 are taken together to form a fused aromatic ring, Y cannot be a ring selected from the group consisting of: ##STR10## PA1 (d) when X, Y and Z, taken together, form a phenanthridone, a phenanthridinone, a phenanthrene, or a phenanthridine nucleus with an amino group or an aminoalkoxylene group in the 3-position, the 8-position cannot also be substituted with an amino group or an aminoalkoxylene group; and PA1 (e) when X, Y and Z, taken together, form a phenanthridinone ring system, the 2-position cannot be either unsubstituted or substituted with a nitro group.
1,2,3,5,-Tetrahydrocyclopenta[c]quinolin-4-one, as cited in Castan et al., "New Arylpiperazine Derivatives with High Affinity for 5-HT.sub.3 Receptor Sites", Med. Chem. Res., 6:2, 81-101 (1996), is an intermediate in the preparation of new arylpiperazine derivatives with high affinity for serotoninergic S.sub.3 receptor sites in relation to structure. However, it is not believed that this intermediate or any of the previously cited oxo-substituted compounds have been shown to inhibit PARP activity.
Other oxo-substituted compounds are disclosed in:
Other structurally distinguishable compounds have been disclosed for medical treatments and other uses. For example, Winter et al., U.S. Pat. No. 4,382,943, discloses the use of dibenzo-[b] [d]pyran-6-one as an antihistamine, an anti-oedematous agent and an antiphlogistic agent. Meyer et al., U.S. Pat. No. 4,169,897, entitled "2,7-Bis-Basic Ethers of 9-Phenanthrol and 9-Loweralkoxy Phenanthrol", discloses certain phenanthrenes and phenanthrinidinones useful for preventing or inhibiting viral infections.
Hunger et al, U.S. Pat. No. 4,082,741, entitled "Disazo Pigments Derived from 3,8-Diamino-Phenanthridone-(10)", discloses compounds useful for pigments suitable for preparing of printing inks, color lacquers and dispersion paints, which are used to dye rubber, plastic materials, and natural or synthetic resins. Montgomery, U.S. Pat. No. 3,291,801, discloses octahydro-6(5)-phenanthridinones that may be converted to the corresponding 6(5)-phenanthridinones, which are useful as intermediates for forming therapeutically active compounds. Hegar, U.S. Pat. No. 3,507,872, entitled "Indolyl-Quinolinium Dyestuffs", discloses water soluble basic dyestuffs comprising .alpha.-pyridones or .gamma.-pyridones.
Schohe et al., U.S. Pat. No. 5,274,097 discloses a number of 1,3-di-substituted pyrrolidines, which can be substituted with, among many others, the following radical: ##STR2##
These structures are said to have high affinity for cerebral 5-hydroxytryptamine receptors of the 5-HT.sub.1 type, which are said to combat diseases distinguished by disturbances of the serotoninergic system, in particular, those involved with receptors having a high affinity for 5-hydroxytryptamine (5-HT.sub.1) type.
The inventors have now discovered that selected oxo-substituted PARP inhibitors can ameliorate neural tissue damage, including that following focal ischemia and reperfusion injury. Generally, inhibition of PARP activity spares perhaps as yet undiscovered, in addition to the production of free radicals and NO.